Newsletter – March 2015 Trimethoprim -‐ Sulfamethoxazole Combined with ACE Inhibitors or Angiotensin II Receptor Blockers Could Raise Risk of Sudden Death in Elderly Written By: Malyssa West – ISU Pharm D Candidate 2016
Hyperkalemia, defined as a serum potassium level above 5.5 mmol/L, is more common in the elderly, and can be fatal when severe.1 Signs and symptoms associated with hyperkalemia include muscle weakness, fainting, upset stomach, fatigue, bradycardia and tachycardia.2 Commonly, patients may lack signs and symptoms of hyperkalemia which may results in the electrolyte abnormality only being discovered though laboratory findings or electrocardiogram (EKG). 2 Dangerous adverse effects of hyperkalemia include cardiac arrhythmias, torsades de pointes, and sudden death.2 Therefore, it should be considered a serious and life-‐threatening condition that requires immediate treatment or implementation of preventative measures in the patient care setting.
Idaho Drug Information Center Idaho State University 921 S. 8th Ave, Stop 8092 Pocatello, ID 83209-8092 208-282-4689 [email protected]
Rebecca Hoover, PharmD, MBA, Director, [email protected]
Location: Third floor Eli Oboler Library at ISU
Combining potassium-‐sparing medications can lead to an increased risk for elderly patients to develop hyperkalemia and possibly hyperkalemia-‐induced arrhythmias.3,4,5 Elderly patients are already at a higher risk for developing drug-‐induced hyperkalemia due to an age-‐related reduction in glomerular filtration rate and decreased activity of the renin-‐angiotensin-‐aldosterone (RAA) system.1 This alone could lead to hyperkalemia, however, most elderly patients diagnosed are on drug therapy that includes a combination of potassium-‐sparing medications.1 Two very common medications prescribed today are angiotensin-‐ converting-‐enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). Primarily these medications are used for the treatment of hypertension, coronary artery disease, congestive heart failure, and chronic kidney disease in the geriatric population.3 Both ACEIs and ARBs are potassium-‐sparing medications and can induce hyperkalemia, with elderly patients having an increased risk of developing this particular adverse reaction.4, 5
Newsletter – March 2015 The combination antibiotic trimethoprim-‐sulfamethoxazole (TMP-‐SMX) is frequently prescribed for treatment of urinary tract infections (UTIs), which are commonly seen in the elderly.3,4,5 Trimethoprim has various similarities with potassium-‐sparing diuretics and, likewise, can impair renal potassium elimination.3,4 Therefore, patients taking TMP-‐SMX develop commonly have increases of serum potassium. As mentioned earlier, severe hyperkalemia can result from taking multiple potassium-‐sparing medications at the same time. Because TMP-‐ SMX, ACEIs, and ARBs are widely used medications in the elderly, the chance of co-‐ administration is extremely high. Independently, these commonly prescribed medications will only have a modest effect on potassium levels. However, combination may result in life threatening hyperkalemia which is often further exacerbated by comorbidities seen in geriatrics.1,2 Population-‐based studies have found that the use of TMP-‐SMX in conjunction with ACEIs or ARBs has been associated with nearly a 7-‐fold increase in the risk of hyperkalemia when compared to using amoxicillin in place of TMP-‐SMX. Although TMP-‐ SMX may be the best choice for the UTI infection, an alternative antibiotic might be a better choice for a patient taking a potassium-‐sparing medication. In practice, TMP-‐SMX is still widely prescribed to elderly patients who are taking ACEs or ARBs. Because of this, sudden death in the elderly can be mistaken for an underlying cardiovascular disease, rather than recognized as hyperkalemia-‐induced arrhythmias associated with the combination of TMP-‐SMX and ACEIs or ARBs.3,4,5 Increased awareness of this drug interaction among pharmacists and physicians is essential. The combination of the potassium-‐sparing medications like TMP-‐SMX, ACEIs, and ARBs should be limited. Options include choosing an alternative antibiotic therapy when possible, reducing dose and duration of TMP-‐SMX treatment, monitoring for abnormal EKGs, and by monitoring serum potassium levels of elderly patients on this drug combination. 3,4,5
Newsletter - March 2015
Hypnotics and Insomnia Refresher
Written By: Ryan Jensen – ISU Pharm D Candidate 2016
Hypnotics are drugs used to induce sleep. There are multiple drug classes that possess the ability to cause hypnosis either as a secondary or primary action. These include antihistamines, benzodiazepines, non-‐benzodiazepine hypnotics, melatonin receptor agonists, antidepressants, barbiturates, anticonvulsants, and antipsychotics.1 The following information below is a summary of different agents and approaches for the treatment of insomnia. General pharmacological stepwise approach for the treatment of insomnia supported by the American A cademy of Sleep Medicine (AASM)1
Step 1 : Short-‐intermediate acting benzodiazepine receptor agonist (BzRA) or ramelteon. BzRA, in this case, is either a classical benzodiazepine or a newer non-‐benzodiazepine hypnotic. The non-‐benzodiazepines appear to have less side effects, dependence, and rebound insomnia than classical benzodiazepines2 Step 2 : Use an alternate BzRA or ramelteon if patient fails the initial treatment. Step 3 : A sedating antidepressant may be considered next if the patient suffers comorbid depression/anxiety or if the patient fails previous treatments. Step 4 : Sedating antiepileptic or antipsychotic drugs may be attempted if the patient has a comorbid condition that benefits from the primary action of the drug. Not recommended for chronic insomnia: OTC antihistamines, analgesics-‐type drugs, herbs, and natural supplements Not recommended for occasional or chronic insomnia: Barbiturates, barbiturate-‐like drugs, and chloral hydrate.
Non-‐Benzodiazepine hypnotics • Used for the onset of sleep only Zolpidem (Ambien®) • Short-‐intermediate acting2 Zolpidem CR (Ambien CR®) Zaleplon (Sonata®) Eszopiclone (Lunesta®)
• • • • • • • • •
10 mg in some patients has risk for daytime drowsiness2 Used for onset and maintenance of sleep 12.5 mg in some patients has risk for daytime drowsiness2 Used for onset of sleep usually (if patient awakes during sleep, may take for maintenance if >4 hours of sleep time remaining)2 Short acting2 This agent can be used long term without restrictions Used for maintenance and onset of sleep Intermediate acting2 Bad aftertaste2,3
Newsletter – March 2015 Benzodiazepines Estazolam (Prosom®)
Flurazepam Lorazepam (Ativan®)
Antidepressants Amitryptyline Doxepin (Silenor®)
• • • • • • • • • • • • • • • •
• • • • • • • • • • •
Used for maintenance and onset of sleep Short-‐intermediate acting2 Avoid with CYP 3A4 inhibitors3 Used for maintenance and onset of sleep Long acting2 Higher risk for daytime drowsiness2 Off-‐label use for maintenance of sleep only4 Used for secondary insomnia due to anxiety2,5 Long acting2 Used for onset and maintenance of sleep Used for onset and maintenance of sleep Short-‐intermediate acting2 No CYP450 interactions and considered better choice for elderly patients2,3 Used for onset of sleep only Higher incidence of rebound insomnia, not considered first line therapy1,2,3 Avoid with CYP 3A4 inhibitors and avoid in elderly2,3
Off label use for comorbid insomnia1 High prevalence of anticholinergic effects1 Use caution in patients with risk or history of cardiac disease Used for maintenance of sleep only No or little rebound insomnia or dependence6 Take 3 hours after meal to avoid delayed absorption and next day drowsiness3 Off label use for comorbid insomnia Less anticholinergic effect than doxepin and amitriptyline2 Risk of restless leg syndrome and weight gain1,6 Off label use Less anticholinergic effect than doxepin and amitriptyline2
Melatonin Receptor Agonist • This agent can be used long term without restrictions1,3 Ramelteon (Rozerem®)
• • • • • •
Used for the onset of sleep only Short acting One of the few hypnotic drugs that shows no dependence2,6 Recently FDA approved for non-‐24-‐hour sleep-‐wake disorder4 Helps reset the circadian cycle when it is too long Specifically for blind patients who have hard time falling and staying asleep
Newsletter - March 2015 Other hypnotic Drugs • OTC antihistamines • •
• • • •
• • •
New drug target
• • •
Agents include diphenhydramine (Benadryl®), doxylamine (Unisom®), and dimenhydrinate (Dramamine®) Anticholinergic effects7 Not recommended for primary insomnia conditions. If used, patients should be counseled to have an “off” night every 3 nights to avoid tolerance7,8 Maximum use should be no more than 2 weeks Agents include butabarbital (Butisol Sodium®) and secobarbital (Seconal®)2,4 Not recommended due to side effect profile, addiction tolerance, and low therapeutic index1,2 Agents include melatonin, valerian, L-‐tryptophan Mildly sedative, not much evidence1,8 Agents include clonazapine, quetiapine, risperidone, chlorpromazine1 May be attempted if the patient has a comorbid condition that benefits from the primary action of the drug1 Agents that may have sedative properties include gabapentin and tiagabine1 Evidence is limited1,8 May be attempted if the patient has a comorbid condition that benefits from the primary action of the drug1 Suvorexant (Belsomra) is an orexin receptor antagonist9 Belsomra approved for insomnia in 2014 and can be used for onset and maintenance of sleep9 Less cognitive impairment and daytime drowsiness than benzodiazepines 9
Key points when using hypnotics 1. 2. 3. 4. 5. 6. 7.
Take on an empty stomach to avoid decreased absorption or delayed onset.1,3 Avoid hypnotics in pregnant or nursing women if possible.1,8 Use with caution in patients who have compromised respiratory function such as COPD and sleep apnea. Also avoid in patients who have signs and symptoms of any depressive disorder.1,3,8 Use with caution in elderly and reduce doses.1,2,3 Counsel patients to avoid ethanol and other CNS depressants due to additive effect with many hypnotics.1,3,6 Avoid in patients who are under the age of 18 due to limited safety and efficacy data in that population.1,4 Avoid sudden or abrupt discontinuation of benzodiazepines due to risk of withdrawal symptoms.1,2,3,8
Newsletter – March 2015 FDA Approves Two Breakthrough Vaccinations for the Prevention of Serogroup B Meningococcal Disease Written by: Sam Zohner – ISU Pharm D Candidate 2016
Within the last six months, the FDA has approved two meningococcal vaccinations. The difference between these two vaccines and all other preceding meningococcal vaccines is their coverage of serogroup B. Before approval, current meningococcal vaccines only covered serogroups A,C,Y, and W-‐135. In the US, serogroups C and Y account for approximately two-‐thirds of invasive meningococcal disease. Serogroup B accounts for roughly one-‐third. Meningococcal disease in general is most common in those aged 16-‐21 years old. Bacterial infection can result in meningitis and/or sepsis. The CDC recommends that children 11-‐12 years of age receive meningococcal conjugate vaccine and receive a booster at age 16. Furthermore, the CDC advices those who may be at higher risk, including first-‐year college students living in residence halls, patients with a damaged or removed spleen, and those traveling to or living in countries in which the disease is common, also receive the vaccine. The CDC has not yet posted guidelines for the use of serogroup B meningococcal vaccines. Below is a table summarizing main differences between the two new meningococcal vaccines and a commonly used tetravalent conjugate vaccine. This chart is not meant to be comprehensive nor in-‐ depth and has not been evaluated by the FDA.
Release date 10/29/14 Effective against serogroup B
Release date 1/23/15 Effective against serogroup B
Form: conjugate vaccine Approved for use in ages 10 -‐ 25 years in the US Three dose series 0, 2, 6 months 0.5ml/dose IM suspension injection, shake before use
Form: conjugate vaccine Approved for use in ages 10 -‐ 25 years in the US Two dose series 0, 1 month
Most common ADR were pain at the injection site (≥85%), fatigue (≥40%), headache (≥35%), muscle pain (≥30%), and chills (≥15%)
Most common ADR were pain at the injection site (≥83%), myalgia (≥48%), erythema (≥45%), fatigue (≥35%), headache (≥33%), induration (≥28%), nausea (≥18%), and arthralgia (≥13%) Pregnancy Category B, only animal studies
Release date 2010 Effective against serogroups A, C, W-‐135 and Y Form: conjugate vaccine Approved for use in ages 2 months -‐ 55 years in the US Depends, see CDC immunization schedule 0.5ml/dose IM injection, Two vials must be combined before use Most common ADR were pain at the injection site (41%), headache (30%), myalgia (18%), malaise (16%) and nausea (10%)
Pregnancy Category B, only animal studies
0.5ml/dose IM suspension injection, shake before use
Pregnancy Category B, only animal studies
Newsletter - March 2015
Trimethoprim -‐ Sulfamethoxazole Combined with ACE Inhibitors or Angiotensin Receptor Blockers Could Raise Risk of Sudden Death in Elderly
Juvet T, Gourineni VC, Ravi S, Zarich SW. Life-‐threatening Hyperkalemia: A Potentially Lethal Drug Combination. Conn Med. 2013 Sep;77(8):491-‐3. PubMed PMID: 24156179.
Lederer, E. Hyperkalemia. In Medscape (Version 4.0) [Mobile application software]. Updated periodically. Accessed 02/28/2015.
Fralick M, Macdonald EM, Gomes T, Antoniou T, Hollands S, Mamdani MM, Juurlink DN; Canadian Drug Safety and Effectiveness Research Network. Co-‐trimoxazole and Sudden Death in Patients Receiving Inhibitors of Renin-‐Angiotensin System: Population Based Study. BMJ. 2014 Oct 30;349:g6196. doi: 10.1136/bmj.g6196. PubMed PMID: 25359996.
Antoniou T, Gomes T, Juurlink DN, Loutfy MR, Glazier RH, Mamdani MM. Trimethoprim-‐ Sulfamethoxazole-‐Induced Hyperkalemia in Patients Receiving Inhibitors of the Renin-‐Angiotensin System: A Population-‐Based Study. Arch Intern Med. 2010 Jun 28;170(12):1045-‐9. doi: 10.1001/archinternmed.2010.142. PubMed PMID: 20585070.
Gentry CA, Nguyen AT. An Evaluation of Hyperkalemia and Serum Creatinine Elevation Associated with Different Dosage Levels of Outpatient Trimethoprim-‐Sulfamethoxazole With and Without Concomitant Medications. Ann Pharmacother. 2013 Dec;47(12):1618-‐26. doi: 10.1177/1060028013509973. Epub 2013 Oct 25. PubMed PMID: 24259630.
Ho JM, Juurlink DN. Considerations When Prescribing Trimethoprim-‐Sulfamethoxazole. CMAJ. 2011 Nov 8;183(16):1851-‐8. doi: 10.1503/cmaj.111152. Epub 2011 Oct 11. PubMed PMID: 21989472.
Lam N, Weir MA, Juurlink DN, Gunraj N, Gomes T, Mamdani M, Hackam DG, Jain AK, Garg AX. Hospital Admissions for Hyperkalemia With Trimethoprim-‐S: A Cohort Study Using Health Care Database Codes for 393,039 Older Women With Urinary Tract Infections. Am J Kidney Dis. 2011 Mar;57(3):521-‐3. doi: 10.1053/j.ajkd.2010.11.006. Epub 2011 Jan 8. PubMed PMID: 21216514.
Sulfamethoxazole/Trimethoprim. Micromedex® Healthcare Series [Micromedex 2.0 mobile application software]. Greenwood Village, CO: Thomson Micromedex. Updated periodically. Accessed 02/28/2015.
9. Image (page 1) courtesy of office clip art 10. Image (page 2) courtesy of Frompo.com
Newsletter – March 2015 Hypnotics and Insomnia Refresher 1.
Schutte-‐Rodin S; Broch L; Buysse D; Dorsey C; Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 2008;4(5):487–504.
Brunton L.L, Chabner B.A, Knollmann B.C. Chapter 17: Hypnotics and Sedatives. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-‐Hill, 2011
PL Detail-‐Document, Comparison of Insomnia Treatments. Pharmacist’s Letter/Prescriber’s Letter. July 2014.
U.S. Food and Drug Administration. Dec. 2014. Sleep Disorder (Sedative-‐Hypnotic) Drug Information. Retrieved from http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvides/
Rosenberg RP. Sleep maintenance insomnia: strengths and weaknesses of current pharmacologic therapies. Ann Clin Psychiatry 2006;18:49-‐56.
Mayo Clinic Staff (2014) Prescription sleeping pills: what’s right for you? In: Diseases and conditions: insomnia, Mayo Clinic. Retrieved from http://www.mayoclinic.org/diseases-‐conditions/insomnia/
Kirkwood CK, Melton ST. Chapter 46. Insomnia, Drowsiness, and Fatigue. In: Krinsky DL, Berardi RR, Ferrei S, et al, Eds. Handbook of Nonprescription Drugs. 17th ed. Washington, DC: American Pharmacists Association, 2012:868-‐83.
Arand DL, Bonnet MB (2014). Patient information: Insomnia treatments (Beyond the Basics). In R. Benca(Ed.), UpToDate. Retrieved from http://www.uptodate.com/home/index.html
Reddy A, Puvvada SC, Kommisetti S, et al. Suvorexant: something new for sleep? Acta Neuropsychiatric. 2014 Nov 14:1-‐3.
10. Image (page 3) courtesy of LEF.org
FDA Approves Two Breakthrough Vaccinations for the Prevention of Serogroup B Meningococcal Disease 1.
U.S Food and Drug Administration. Nov. 2014. Trumenba. Approved products. Retrieved from http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM421139 .pdf U.S Food and Drug Administration. Jan. 2015. Bexsero. Approved products. Retrieved from http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM431447 .pdf
U.S Food and Drug Administration. 2011. Menveo. Approved products. Retrieved from http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM201349 .pdf
Centers for Disease Control and Prevention (CDC). April 2014. Meningococcal vaccination. Meningococcal disease. Retrieved from http://www.cdc.gov/meningococcal/